Oral clefts are among the most common birth defects and are generally more prevalent in Asia than elsewhere. The burden of oral clefts is great because affected children require substantial medical care and may live long lives with disabilities. Our long-term goal is to elucidate the role of common maternal nutritional and metabolic factors in oral clefts as a prerequisite to developing preventive measures. Maternal biomarkers related to one-carbon metabolism (1-CM) including folate, zinc, vitamin B-6, and homocysteine have been associated with risk of oral clefts- but several inconsistencies require clarification before public health interventions are initiated. Type 2 diabetes mellitus is a global public health threat and has been associated with an increased risk of birth defects though its role in oral clefts is uncertain. International studies in Asia are efficient because many populations there have a high risk of oral clefts and exposure characteristics are variable across geographic areas, increasing the probability of detecting meaningful associations. A two-year planning project is proposed to develop a multi-center, population-based, case-control study of maternal nutritional and metabolic factors in oral clefts in the Philippines, Singapore, Taiwan, and China. In the full scale study the following hypotheses will be tested: (1) maternal biomarkers related to 1-CM including folate, zinc, vitamins B6 and B12, and homocysteine are each independently associated with risk of oral clefts;(2) 1-CM biomarkers interact to influence oral cleft risk;(3) impaired glucose tolerance and diabetes are each associated with risk of oral clefts;(4) impaired 1-CM and impaired glucose tolerance and diabetes interact to increase risk of oral clefts. Specific Aims: 1) Develop the refined study design;(2) Develop the organizational structures and plans at each study site and the coordinating center;(3) Complete detailed study protocols and materials and pilot-test at each site. Completion of these specific aims will result in enhanced international collaborative partnerships, infrastructure, study materials, and a submitted R01 application for the full study by the end of the planning project. PUBLIC HEALTH RELEVANCE: Oral clefts are among the most common birth defects and the public health burden is great because affected children require substantial medical care and may live long lives with disabilities. The long-term goal of our research team is to elucidate the role of common maternal nutritional and metabolic factors in oral clefts as a prerequisite to developing preventive measures.